ABSTRACT Chronic Pelvic Pain (CPP) is a debilitating problem that afflicts 15-20% of women in the United States. Although over 200,000 hysterectomies are performed annually for the treatment of CPP, 1 in 4 women undergo the discomfort and morbidity of hysterectomy without relief of pain. Factors that predict treatment failure remain poorly characterized. While the pathogenesis of CPP is not fully understood, the best-supported hypothesis is that CPP is a heterogeneous condition that results from a complex interaction between pathology in peripheral tissues (e.g. endometriosis), the peripheral nervous system (PNS), and the central nervous system (CNS), each with variable contribution in any given patient with CPP. Preliminary data presented in this application confirms that a subset of women with CPP exhibit evidence of peripheral and central sensitization. What remains unclear is how peripheral and central factors interact to maintain CPP, and whether measures of peripheral and central sensitization prior to hysterectomy can be used to guide clinical care in these women. The long-term goal is to understand the interplay between peripheral pathology and peripheral and central neurobiological dysfunction in women with CPP so that personalized treatment strategies can be developed for individual patients. The objective of this study is to characterize role of peripheral and central sensitization among women undergoing hysterectomy for CPP and to explore the utility of preoperative measures of PNS and CNS factors to predict the likelihood of persistent post-hysterectomy pain. This prospective observational study will recruit 250 women over 4 years who are scheduled to undergo hysterectomy, 200 for the treatment of CPP, 50 pain-free controls. Preoperative measures of central sensitization (self-report measures, quantitative sensory testing, neuroimaging), peripheral sensitization (endometrial nerve fiber density, neurotrophins and proinflammatory cytokines), and psychosocial factors will be assessed. Patients will be followed at regular intervals for 6 months to assess pain symptoms and related surgical outcomes. Our central hypothesis is that preoperative factors associated with central sensitization predict failure of hysterectomy to relieve pain, whereas findings associated with peripheral sensitization predict a higher likelihood of pain relief from hysterectomy, since hysterectomy is likely to remove the peripheral pathology that maintains peripheral sensitization. The approach is innovative because it will use state-of-the-art methods to simultaneously determine the relative contributions of both peripheral and central factors that maintain CPP and failure of hysterectomy to cure pain. These results will have a significant positive impact in women's health because they will have broad implications for the development of a personalized, mechanism-based treatment strategy for CPP, which may also be applicable to other chronic pain states. Not only will we be able to identify which individuals with CPP are not likely to benefit from surgery, these results will help develop algorithms for choosing the correct combinations of peripherally- and centrally-directed treatments for individual patients with chronic pain.